Robert J. Deeth

Bio: Robert J. Deeth is an academic researcher from University of Warwick. The author has contributed to research in topics: Ligand field theory & Density functional theory. The author has an hindex of 40, co-authored 189 publications receiving 5356 citations. Previous affiliations of Robert J. Deeth include Academy of Sciences of the Czech Republic & University of Bath.

Discovery of a new peptide natural product by Streptomyces coelicolor genome mining.

Abstract: Analyses of microbial genome sequences reveal numerous examples of gene clusters encoding proteins typically involved in complex natural product biosynthesis but not associated with the production of known natural products. In Streptomyces coelicolor M145 there are several gene clusters encoding new nonribosomal peptide synthetase (NRPS) systems not associated with known metabolites. Application of structure-based models for substrate recognition by NRPS adenylation domains predicts the amino acids incorporated into the putative peptide products of these systems, but the accuracy of these predictions is untested. Here we report the isolation and structure determination of the new tris-hydroxamate tetrapeptide iron chelator coelichelin from S. coelicolor using a genome mining approach guided by substrate predictions for the trimodular NRPS CchH, and we show that this enzyme, which lacks a C-terminal thioesterase domain, together with a homolog of enterobactin esterase (CchJ), are required for coelichelin biosynthesis. These results demonstrate that accurate prediction of adenylation domain substrate selectivity is possible and raise intriguing mechanistic questions regarding the assembly of a tetrapeptide by a trimodular NRPS.

Controlling ligand substitution reactions of organometallic complexes: tuning cancer cell cytotoxicity.

Abstract: Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional “piano-stool” ruthenium(II) arene complexes of the type [(η6-arene)Ru(ethylenediamine)(X)]n+. A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents.

Osmium(II) and Ruthenium(II) Arene Maltolato Complexes: Rapid Hydrolysis and Nucleobase Binding

Abstract: Density functional calculations show that aquation of [Os(eta(6)-arene)(XY)Cl](n+) complexes is more facile for complexes in which XY=an anionic O,O-chelated ligand compared to a neutral N,N-chelated ligand, and the mechanism more dissociative in character The O,O-chelated XY=maltolato (mal) [M(eta(6)-p-cym)(mal)Cl] complexes, in which p-cvm=p-cymene, M=Os-II (1) and Run (2) were synthesised and the X-ray crystal structures of I and 2-2H(2)O determined Their hydrolysis rates were rapid (too fast to follow by NMR spectroscopy) The aqua adduct of the Os-II complex 1 was 16 pK(a) units more acidic than that of the Ru-II complex 2 Dynamic NMR studies suggested that O,O-chelate ring opening occurs on a millisecond timescale in coordinating proton-donor solvents, and loss of chelated mal in aqueous solution led to the formation of the hydroxo-bridged dimers [(eta(6)-p-cyrn)M(mu-OH)(3)M(eta(6)-p-cym)](+) ne proportion of this dimer in solutions of the Os-II complex 1 increased with dilution and it predominated at micromolar concentrations, even in the presence of 01 M NaCl (conditions close to those used for cytotoxicity testing) Although 9-ethylguanine (9-EtG) binds rapidly to Os-II in 1 and more strongly (log K=44) than to Ru-II in 2 (log K=39), the Os-II adduct [Os(eta(6)-p-cym)(mal)-(9EtG)](+) was unstable with respect to formation of the hydroxo-bridged dimer at micromolar concentrations Such insights into the aqueous solution chemistry of metal-arene complexes under biologically relevant conditions will aid the rational design of organometallic anticancer agents

A Unified Treatment of the Relationship Between Ligand Substituents and Spin State in a Family of Iron(II) Complexes.

Abstract: The influence of ligands on the spin state of a metal ion is of central importance for bioinorganic chemistry, and the production of base-metal catalysts for synthesis applications. Complexes derived from [Fe(bpp)2]2+ (bpp=2,6-di{pyrazol-1-yl}pyridine) can be high-spin, low-spin, or spin-crossover (SCO) active depending on the ligand substituents. Plots of the SCO midpoint temperature (Tinline image ) in solution vs. the relevant Hammett parameter show that the low-spin state of the complex is stabilized by electron-withdrawing pyridyl (“X”) substituents, but also by electron-donating pyrazolyl (“Y”) substituents. Moreover, when a subset of complexes with halogeno X or Y substituents is considered, the two sets of compounds instead show identical trends of a small reduction in Tinline image for increasing substituent electronegativity. DFT calculations reproduce these disparate trends, which arise from competing influences of pyridyl and pyrazolyl ligand substituents on Fe-L σ and π bonding.

Theoretical Modeling of Water Exchange on [Pd(H2O)4]2+, [Pt(H2O)4]2+, and trans-[PtCl2(H2O)2]

Abstract: SynopsisOptimized structures describing key features of the potential energy surface for water exchange at three planar d8 centers have been calculated using ab initio density functional theory. The local density approximation (LDA), including relativistic corrections for Pt, gives good agreement with the available experimental ground state structural data. LDA binding energies together with explicit hydration enthalpy estimates confirm an associative mechanism, yield theoretical activation enthalpies within about 15 kJ/mol of the reported ΔH⧧ values, and indicate extensive bond stretching in the transition state, compatible with the observed small negative ΔV⧧ values.AbstractDensity functional theory is applied to modeling the exchange in aqueous solution of H2O on [Pd(H2O)4]2+, [Pt(H2O)4]2+, and trans-[PtCl2(H2O)2]. Optimized structures for the starting molecules are reported together with trigonal bipyramidal (tbp) systems relevant to an associative mechanism. While a rigorous tbp geometry cannot by symmetry be the actual transition state, it appears that the energy differences between model tbp structures and the actual transition states are small. Ground state geometries calculated via the local density approximation (LDA) for [Pd(H2O)4]2+ and relativistically corrected LDA for the Pt complexes are in good agreement with available experimental data. Non-local gradient corrections to the LDA lead to relatively inferior structures. The computed structures for analogous Pd and Pt species are very similar. The equatorial M−OH2 bonds of all the LDA-optimized tbp structures are predicted to expand by 0.25−0.30 A, while the axial bonds change little relative to the planar precursors. This bond stretching in the transition state counteracts the decrease in partial molar volume caused by coordination of the entering water molecule and can explain qualitatively the small and closely similar volumes of activation observed. The relatively higher activation enthalpies of the Pt species can be traced to the relativistic correction of the total energies while the absolute ΔH⧧ values for exchange on [Pd(H2O)4]2+ and [Pt(H2O)4]2+ are reproduced using relativistically corrected LDA energies and a simple Born model for hydration. The validity of the latter is confirmed via some simple atomistic molecular mechanics estimates of the relative hydration enthalpies of [Pd(H2O)4]2+ and [Pd(H2O)5]2+. The computed ΔH⧧ values are 57, 92, and 103 kJ/mol compared to experimental values of 50(2), 90(2), and 100(2) kJ/mol for [Pd(H2O)4]2+, [Pt(H2O)4]2+, and trans-[PtCl2(H2O)2], respectively. The calculated activation enthalpy for a hypothetical dissociative water exchange at [Pd(H2O)4]2+ is 199 kJ/mol. A qualitative analysis of the modeling procedure, the relative hydration enthalpies, and the zero-point and finite temperature corrections yields an estimated uncertainty for the theoretical activation enthalpies of about 15 kJ/mol. (Less)

Effect of the damping function in dispersion corrected density functional theory

Abstract: It is shown by an extensive benchmark on molecular energy data that the mathematical form of the damping function in DFT-D methods has only a minor impact on the quality of the results. For 12 different functionals, a standard "zero-damping" formula and rational damping to finite values for small interatomic distances according to Becke and Johnson (BJ-damping) has been tested. The same (DFT-D3) scheme for the computation of the dispersion coefficients is used. The BJ-damping requires one fit parameter more for each functional (three instead of two) but has the advantage of avoiding repulsive interatomic forces at shorter distances. With BJ-damping better results for nonbonded distances and more clear effects of intramolecular dispersion in four representative molecular structures are found. For the noncovalently-bonded structures in the S22 set, both schemes lead to very similar intermolecular distances. For noncovalent interaction energies BJ-damping performs slightly better but both variants can be recommended in general. The exception to this is Hartree-Fock that can be recommended only in the BJ-variant and which is then close to the accuracy of corrected GGAs for non-covalent interactions. According to the thermodynamic benchmarks BJ-damping is more accurate especially for medium-range electron correlation problems and only small and practically insignificant double-counting effects are observed. It seems to provide a physically correct short-range behavior of correlation/dispersion even with unmodified standard functionals. In any case, the differences between the two methods are much smaller than the overall dispersion effect and often also smaller than the influence of the underlying density functional.

Natural Products as Sources of New Drugs over the Last 25 Years

Abstract: This review is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003. In the case of all approved agents the time frame has been extended to include the 251/2 years from 01/1981 to 06/2006 for all diseases worldwide and from 1950 (earliest so far identified) to 06/2006 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 155 small molecules, 73% are other than “S” (synthetic), with 47% actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the antiinfective area ...

The heck reaction as a sharpening stone of palladium catalysis.

Abstract: s, or keywords if they used Heck-type chemistry in their syntheses, because it became one of basic tools of organic preparations, a natural way to